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Areas of Investigation

Research in our laboratory focuses on molecular mechanisms of plasticity and neurodegeneration. A long-term goal of our research is to understand how neuronal activity elicits changes in gene expression that are important for learning and memory. Memory disturbances occur in several neurodegenerative diseases, and we have developed models of several of them including Huntington’s disease (HD), Parkinson’s Disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. A better understanding of the mechanisms that control memory formation and neurodegeneration will yield crucial insights into the pathogenesis of neurodegenerative diseases and the memory disorders that often characterize them.

Lab Focus

Which genes are critical for forming memories and how do they do so?

How do genetic mutations in selected genes lead to elective degeneration in certain types of neurons in HD, PD, and ALS?

What are the critical coping mechanisms that brain cells generate to mitigate the effects of genetic mutations that cause neurodegeneration?

With our unique robotic microscope technology, can we identify the major determinants of cell fate during normal development of stem cells and in neurodegenerative disease?

How can we effectively advance the discoveries we make in the laboratory into medicines to help patients?

Achievements

Found that proteins bound to the cytoplasmic portion of one subtype of glutamate receptor, the N-methyl-D-aspartate receptor, play a critical role coupling local calcium influx through the channel to elicit adaptive gene transcription in neurons. This may be a general mechanism by which diverse calcium channels achieve specific and distinct neuronal responses.

Developed primary culture models of activity-dependent gene transcription and of HD. These models faithfully recapitulate critical features of these processes and allow us to test hypotheses about their underlying mechanisms.

Showed that the nucleus is a critical subcellular site in which mutant huntingtin induces neurodegeneration. However, mutant huntingtin need not aggregate into inclusions to induce neurodegeneration.

Developed an automated imaging system that we call a “robotic microscope.” This instrument enables us to track living neurons over long time periods to quickly quantify the adaptive or maladaptive responses of thousands of neurons. Along with special statistical methods, we now have the ability to determine whether and to what extent a variable that is observed on one day can predict the fate of that neuron on another day. This ability will enable us to unravel confounding cause-and-effect mechanisms.

Affiliations

Director, Hellman Family Foundation Alzheimer’s Disease Research Program

American Neurological Association

Society for Neuroscience

American Society for Cell Biology

Biophysical Society

Vertex Pharmaceuticals (Scientific Advisory Board)

LINK Medicine (Scientific Advisory Board)

FivePrime Therapeutics, Inc. (Consultant)

Professional titles

Director, Taube/Koret Center for Neurodegenerative Disease Research and